U.S. patent number 7,749,529 [Application Number 11/053,130] was granted by the patent office on 2010-07-06 for catheter lock solution comprising citrate and a paraben.
This patent grant is currently assigned to Ash Access Technology, Inc.. Invention is credited to Stephen R. Ash, Janusz Steczko, Gary L. Swanson.
United States Patent |
7,749,529 |
Ash , et al. |
July 6, 2010 |
Catheter lock solution comprising citrate and a paraben
Abstract
This invention relates to compositions, methods, devices and
kits relating to the infusion of a catheter lock solution into an
indwelling catheter. Inventive compositions, methods, devices and
kits aid in diminishing the effects of microbial infection in
catheters and occlusion of the catheters. A lock solution provided
by the invention includes citrate and a paraben. The solution
preferably has a density suitable for retention of the solution in
a catheter during the lock period. Another lock solution provided
by the invention includes citrate, a paraben and a photo-oxidant,
such as, for example, methylene blue.
Inventors: |
Ash; Stephen R. (Lafayette,
IN), Steczko; Janusz (West Lafayette, IN), Swanson; Gary
L. (Elkhorn, WI) |
Assignee: |
Ash Access Technology, Inc.
(West Lafayette, IN)
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Family
ID: |
36563297 |
Appl.
No.: |
11/053,130 |
Filed: |
February 8, 2005 |
Prior Publication Data
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Document
Identifier |
Publication Date |
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US 20060177477 A1 |
Aug 10, 2006 |
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Current U.S.
Class: |
424/423; 604/500;
514/533; 514/574; 514/224.8 |
Current CPC
Class: |
A61P
31/04 (20180101); A61L 29/14 (20130101); A01N
37/04 (20130101); A61P 31/00 (20180101); A61P
7/02 (20180101); A61L 29/16 (20130101); A01N
37/10 (20130101); A61P 7/08 (20180101); A61M
25/0017 (20130101); A61L 2300/404 (20130101); A61L
2300/42 (20130101) |
Current International
Class: |
A61K
31/5415 (20060101); A61K 31/19 (20060101); A61K
31/235 (20060101); A61F 2/00 (20060101) |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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H04-502324 |
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Apr 1992 |
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JP |
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WO 90/06759 |
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Jun 1990 |
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WO |
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WO 00/01391 |
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Jan 2000 |
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WO |
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WO 00/10385 |
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Mar 2000 |
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WO |
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WO 01/85249 |
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Nov 2001 |
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WO |
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Primary Examiner: Sheikh; Humera N
Assistant Examiner: Al-Awadi; Danah
Attorney, Agent or Firm: Leydig, Voit & Mayer, Ltd.
Claims
What is claimed is:
1. A method of inhibiting infection in an indwelling catheter
defining at least one lumen therethrough, the method comprising
infusing an aqueous catheter lock solution into a lumen of the
catheter, the solution comprising citrate, methylene blue and a
paraben dispersed or dissolved therein.
2. The method of claim 1 wherein the catheter is an intravascular
catheter or a body cavity catheter.
3. The method of claim 1 wherein the lumen of the catheter has an
internal volume and the method comprises infusing an amount of the
lock solution that is from about 80% to about 120% of the internal
volume of the lumen.
4. The method according to claim 1 wherein the paraben is methyl
paraben, ethyl paraben, propyl paraben, butyl paraben, or a
combination thereof.
5. The method according to claim 1 wherein the solution comprises
methyl paraben.
6. The method according to claim 5 wherein the concentration of
methyl paraben in the solution is from about 0.005 to about 0.5
percent.
7. The method according to claim 1 wherein the solution comprises
propyl paraben.
8. The method according to claim 7 wherein the concentration of
propyl paraben in the solution is from about 0.005 to about 0.5
percent.
9. The method according to claim 1 wherein the solution comprises
methyl paraben and propyl paraben.
10. The method according to claim 9 wherein the concentration of
methyl paraben in the solution is from about 0.05 to about 0.5
percent and the concentration of propyl paraben in the solution is
from about 0.005 to about 0.5 percent.
11. The method according to claim 1 wherein the concentration of
citrate in the solution is at least as high as the calcium
concentration in a patient's blood.
12. The method according to claim 1 wherein the concentration of
citrate in the solution is from about 1.5 to about 47% by
weight.
13. The method according to claim 1 wherein the concentration of
citrate in the solution is from about 1.5 to about 23% by
weight.
14. The method of according to claim 1 wherein the citrate has a
concentration of from about 1.5 to about 15 percent and the paraben
has a concentration of from about 0.005 to about 0.6 percent.
15. The method according to claim 1 wherein the citrate is
trisodium citrate dihydrate.
16. The method according to claim 1 wherein the pH of the solution
is from about 4 to about 8.
17. The method according to claim 1 wherein the relative density of
the solution is from about 1.000 to about 1.300 g/ml.
18. The method according to claim 1 wherein the solution further
comprises a viscosifying agent.
19. The method according to claim 18 wherein the viscosifying agent
comprises dextran, polyethylene glycol, glycerin, polygeline, a
non-metabolizable sugar, or a combination thereof.
20. The method according to claim 1 wherein the concentration of
methylene blue in the solution is up to about 1500 mg/100 ml.
21. The method according to claim 1, wherein the catheter is in a
patient.
22. The method according to claim 21, wherein the catheter is
surgically implanted.
Description
BACKGROUND
This invention generally relates to catheters and methods of
preventing occlusion and infection of catheters, such as
intravascular catheters and other body cavity catheters. More
specifically, but not exclusively, this invention relates to
infusing a lock solution into an indwelling catheter, such as, for
example, an indwelling intravascular catheter, for inhibiting
occlusion and infection in an animal having an indwelling
catheter.
By way of background, catheters are used with increasing frequency
to treat patients requiring a variety of medical procedures.
Catheters offer many advantages for patients; for example,
catheters provide ready access to a patient's vasculature without
repeated injections for infusion of fluids such as drugs,
nutrients, electrolytes or fluids used in chemotherapy, or for the
removal of blood on an intermittent basis. In hyperalimentation
treatment, catheters are usually used for infusion of large volumes
of fluids. In chemotherapy, catheters are used for infusion of
drugs on an intermittent basis, ranging from daily to weekly. For
hemodialysis, dual-lumen catheters are typically used--usually
three times per week--to remove blood from the patient's
circulatory system for treatment and to return treated blood back
to the patient. One lumen allows removal of blood, while the other
lumen allows blood to return.
Catheters are also used to perform other functions and to convey
fluids into and out of other body cavities besides veins, as noted
above. For example, catheters are placed into arteries to measure
blood pressure or remove arterial blood for analysis of gases
reflecting lung function; catheters are placed into the peritoneum
(the space surrounded by the peritoneal membrane and external to
organs in the abdomen) to perform peritoneal dialysis and remove
fluids and toxins from the patient; and other catheters are placed
into the fluid around the nervous system (cerebral spinal fluid)
for removal of this fluid or administration of drugs, and into the
subcutaneous space for administration of various drugs or fluids.
Such catheters are also subject to infection and to other problems
addressed herein.
Catheters can either be acute, or temporary, for short-term use or
chronic for long-term treatment. Catheters used to access a
patient's bloodstream are commonly inserted into central veins
(such as the vena cava) from peripheral vein sites. Another
alternative is placement of a dual-lumen chronic central venous
dialysis catheter (a "CVDC") through the internal jugular vein.
Adequate hemodialysis requires removal and return of 250-400 mL of
blood per minute.
Catheters, especially chronic venous catheters, have drawbacks. The
use of both temporary and chronic CVDCs is associated with certain
complications that may require catheter removal, catheter
replacement and/or administration of medical therapies. They can
become occluded by a thrombus, and even if extreme care is taken,
the catheters can increase a patient's risk of infection.
Considering first the problem of infection, great care must be
taken in the placement and use of a chronic catheter to prevent
infection of the patient at the site of access or within the
vascular system. The foreign surfaces of catheters can create
smooth surfaces at which bacteria can grow, and at which white
cells are unable to surround or "phagocytize" the bacteria. One way
that a catheter, particularly a chronic catheter such as a CVDC,
can give rise to infection is by the migration of bacteria around
the catheter across the protective dermal layers. To address this
problem, a chronic CVDC usually includes a DACRON cuff attached to
the catheter and placed under the skin, which promotes ingrowth of
fibrous tissue, fixes the catheter in position, and prevents
bacterial migration around the catheter. Most chronic CVDCs in use
in the U.S. today have single subcutaneous Dacron.RTM. cuffs,
placed in the tunnel, 1-4 cm beneath the skin exit site. For dual
lumen catheters such as the Ash Split Cath.TM. and Bard
Hickman.RTM. catheters, there is one cuff on the catheter. For
single-lumen catheters such as Tesio.RTM. catheters, there is a
single Dacron cuff for each catheter. Cuffed, tunneled CVDCs have a
decrease in the rate of exit site infection and catheter-related
bloodstream infection ("CRBSI") versus uncuffed catheters, but
these infections still occur. It is believed that the only chronic
CVDC in the U.S. at present that does not have a subcutaneous
Dacron cuff is the Schon.TM. catheter. In this catheter a
subcutaneous plastic clip connects two Tesio catheters. This clip
fixes the catheters in position and apparently prevents
pericatheter bacterial migration in a manner similar to a Dacron
cuff. Chronic CVDCs are typically made from one of three types of
materials: silicone, polyurethane, or polyurethane derivatives.
For chronic CVDC the most common cause of catheter infection is
contamination of the connector hub, and the predominant route of
contamination is endoluminal. Catheters, particularly venous
catheters, are frequently accessed with syringes, or uncapped and
directly connected to IV lines, creating a situation wherein the
probability of microbial infection is relatively high. The major
determinant of the rate of infection is the frequency with which
the catheter hub is opened and the major preventive step is the
care in disinfection of the hub and prevention of contamination of
the hub. Since endoluminal contamination is the major cause of
CRBSI in chronic CVDC, the determinants of infection center on the
procedures and handling of the catheter.
Several studies have indicated a rate of bloodstream infection
during use of chronic CVDC of 1.1 to 2.2 per 1,000 patient days.
One study demonstrated a catheter-related bacteremia rate of 2.2 to
3.8 bacteremic episodes per 1,000 patient days, the lower rate
being for catheters placed surgically rather than radiologically.
Another study of new tunneled catheters reported that 19% of
catheters became infected in a mean of 62 days after catheter
placement, representing a rate of 3 infections per 1,000 days. This
means that each patient has approximately a 10% chance of
developing bloodstream infection during each month. There is no
evidence that the rate of CRBSI increases with duration of use of a
chronic CVDC. In fact, practical experience and various studies
have shown that the rate of CRBSI is the same over the many months
of use. Tests indicate that the risk of CRBSI is the same for each
period of time that the patient has a catheter. Over time the
patient has a higher chance for infection merely because there is
more time at risk for infection. The longer the patients have a
chronic CVDC, the greater the chance that an infection will occur,
but this is merely due to greater time for a constant risk of
exposure.
CRBSI in dialysis patients is usually associated with modest
symptoms and clears after antibiotic therapy. However, in some
patients, signs of infection are much more severe and include all
of the symptoms of Systemic Inflammatory Response Syndrome ("SIRS")
(tachycardia, tachypnea, abnormal temperature and white count) plus
hypotension. Often these patients must be hospitalized and given
intravenous antibiotics. In spite of this care, patients often
remain seriously ill until the infected catheter is removed.
Studies have shown that CRBSI in hemodialysis patients is caused
most frequently by Staphylococcus species such as S. Epidermidis.
However, hemodialysis patients are reported to have a greater
proportion of CRBSIs due to S. Aureus than do other patient
populations and a significant number of infections are due to
gram-negative organisms.
The mortality rate following CRBSI in ICU patients has been
reported to be 3-25%. It was reported in a recent year that about
60,000 of the 300,000 patients on dialysis in the U.S. had chronic
CVDC. Assuming an average incidence of CRBSI of only 21,000
patient-days at risk, about 120 of these patients would be expected
to develop CRBSI each day. At the lowest reported mortality rate of
3%, 3-4 ESRD patients die from CRBSI each day. At the highest
reported mortality of 25%, 30 ESRD patients die from CRBSI each
day. Furthermore, the cost attributable to caring for a single
CRBSI episode in hospitalized patients has been reported to be
between $3,700 and $29,000. Costs may be higher for patients with
CRBSI related to chronic CVDC, given the higher cost of removing
and replacing a chronic CVDC. Given the serious consequences of
CRBSI, the acute illness of the patient who apparently has
bacteremia, and the frequent decision to remove the catheter on the
presumption that it is the source, there is a great need for
alternative means for fighting catheter infection.
Turning now to the problem of catheter occlusion, intraluminal
thrombus formation can significantly impair catheter flow, as can
thrombus formation just outside the tip of the catheter. Impairment
of the flow may lead to catheter removal or administration of drugs
such as tPA to resolve these thromboses. In order to prevent
clotting of catheters in blood vessels between uses of a CVDC,
catheters have commonly been filled with a lock solution that
comprises a concentrated solution of the commonly used
anticoagulant, heparin (usually up to 10,000 units of heparin per
catheter lumen). The heparin lock solution is injected into each
lumen immediately after each use, and typically left in the
catheter until the catheter is accessed again. The heparin lock
solution is then withdrawn from the catheter before the next use
because infusing this amount of heparin into a patient's
bloodstream runs the risk of causing excessive bleeding. During the
catheter lock procedure the injected volume of solution is
preferably exactly the same as the internal volume of the catheter.
Even when this volume is injected exactly, however, about 1/3 of
the injected anticoagulant volume typically leaves the end of the
catheter, causing some systemic anticoagulation of the patient in
the hours after a dialysis procedure.
Even with the use of a heparin lock solution, the catheter can
become occluded between uses from coagulation of blood in the
catheter. Blood may be found in the catheter because, for example,
an inadequate volume of heparin was originally infused within the
catheter lumen, the heparin diffused or convected from the lumen,
or residual blood remains in the lumen during the catheter lock.
This often results in formation of a thrombus with concomitant loss
of flow through the lumen. The occluded catheters frequently must
be removed and/or replaced.
Furthermore, it has been reported that thrombi and fibrin deposits
on catheters may serve as a nidus for microbial colonization of the
intravascular devices, and that catheter thrombosis might therefore
be one factor associated with infection of long-term catheters.
Thus, the use of anticoagulants or thrombolytic agents may have a
role in the prevention of catheter-related bloodstream infections.
However, recent in vitro studies suggest that the growth of
coagulase-negative Staphylococci on catheters may also be enhanced
in the presence of heparin. In addition, the routine use of heparin
to maintain catheter patency, even at doses as low as 250 to 500
units per day, has caused some patients with anti-heparin
antibodies to experience heparin-induced thrombocytopenia (HIT
Syndrome). This serious syndrome can result in severe and sudden
thromboembolic and hemorrhagic complications.
Heparin solutions have no proven intrinsic antiseptic properties to
prevent infection after catheter hub contamination. The lack of
antiseptic properties of a 5000 U/mL heparin lock was confirmed by
a study performed by BEC Laboratories, Inc. under the standard USP
antimicrobial effectiveness test protocol. "Antiseptic", as used
herein, means "relating to the prevention of infection by
inhibiting the growth of infectious agents", as defined in
Stedman's medical dictionary. Heparin, in fact, may help to promote
growth of bacteria within the "biofilm" layer of protein on the
catheter surfaces (protamine has the opposite effect). The
"biofilm" proteins on the catheter surfaces can protect bacteria
from antibiotics and white cells. Also, heparin induces the loss of
platelets and, paradoxically, can induce clotting in some patients
(the "white clot" syndrome).
In order to achieve a catheter lock solution that is resistant to
clotting and resistant to microbial infection, some have proposed
the inclusion of antibiotics in heparin lock solutions or
prophylactic systemic delivery of antibiotics to patients with
CVDCs. However, because of frequent hospitalizations and receipt of
antibiotics to treat bloodstream and vascular access infections,
hemodialysis patients are at high risk for infection with
drug-resistant bacteria. The rapid increase in vancomycin-resistant
enterococci (VRE) in the United States has been attributed to use
of antimicrobials, especially empirically prescribed vancomycin.
Vancomycin is used commonly in dialysis patients for empiric
therapy of symptoms of bloodstream infection because it can be
administered once a week and is effective against two common
pathogens, coagulase-negative Staphylococci and Staphylococcus
Aureus. The greater the use of vancomycin, however, the greater the
risk of inducing vancomycin-resistant staphylococcus, and if this
is the cause of septicemia, there are then no effective drugs with
which to treat these patients. Use of prophylactic vancomycin and
other antibiotics to prevent catheter infection is therefore
discouraged, and alternate means for fighting catheter infection
are greatly needed.
Significant resources are currently being invested in a search for
alternatives to heparin for catheter lock that do not have the
above disadvantages, and for catheter formulations that have
antimicrobial properties without including antibodies. For example,
the present inventor has previously described catheter lock
solutions including antimicrobial concentrations of citrate.
Citrate provides effective anticoagulant properties when used in a
catheter lock solution and, at a high concentration (i.e., at about
47% by weight), citrate also provides effective antimicrobial
properties. One challenge presented by such a solution is that the
high specific gravity of a concentrated citrate solution makes the
solution tend to "run out" of a catheter over time. In addition,
there are potential serious side effects if highly concentrated
citrate is infused into a patient's bloodstream. These problems can
be reduced by lowering the concentration of citrate in the
solution, and even low concentrations of citrate have been shown to
be at least equal to heparin in terms of maintaining catheter
patency; however, lowering the concentration of citrate does result
in a decrease in antimicrobial effects.
In light of the above-described problems, there is a continuing
need for advancements in the field of catheter lock solutions. The
present invention addresses this need and provides a wide variety
of benefits and advantages.
SUMMARY
In one form, the invention provides an aqueous catheter lock
solution comprising citrate and a paraben dispersed or dissolved
therein. The citrate and the paraben preferably have concentrations
effective to eliminate infection and to reduce the likelihood of
subsequent infections. In alternative forms of the invention, the
paraben is methyl paraben, propyl paraben, a combination of methyl
paraben and propyl paraben, or any one of or a mixture of methyl
paraben, ethyl paraben, propyl paraben and butyl paraben. When the
term "butyl" is used herein, it is intended to refer to any of four
isomeric monovalent radicals C.sub.4H.sub.9 derived from butanes.
The citrate can advantageously be provided in the form of trisodium
citrate dihydrate or other citrate salt. The relative density of
the solution is selected in certain embodiments to be similar to
the relative density of a patient's blood, and to thereby optimize
the length of time that the solution remains in a catheter. The
solution in other embodiments also includes a viscosifying agent
and/or additional pharmaceutically acceptable materials. In one
particularly preferred embodiment, a catheter lock solution is
provided that includes citrate, a paraben and a photo-oxidant
having antimicrobial effect. One photo-oxidant that has been shown
by the inventors to have excellent antimicrobial properties is
methylene blue.
In another form, the present invention provides a method for
treating patients having an indwelling intravascular catheter. In
one embodiment, the method comprises selecting a patient having an
indwelling catheter defining a lumen therethrough; and infusing an
aqueous catheter lock solution into the lumen, the solution
comprising citrate and a paraben dispersed or dissolved therein.
The invention is particularly useful in treating a patient having
an infection or a substantial risk of infection related to the
presence of the catheter.
In yet another form of the invention, there is provided an infusion
device for infusing a lock solution into a lumen of a catheter. The
device includes a syringe and a pharmaceutically acceptable lock
solution contained within the syringe. The lock solution includes
citrate and a paraben dispersed or dissolved therein. In a
preferred embodiment, the syringe containing the lock solution is
sterilized.
The invention also provides a method of treating animals having a
surgically implanted catheter. The method includes infusing into
the catheter a pharmaceutically acceptable lock solution comprising
a bactericidal component that consists essentially of citrate and a
paraben. In a preferred embodiment, the bactericidal component does
not include an antibiotic.
In still another form, the invention provides devices, methods and
compositions relating to the pretreatment of a catheter or other
medical implant prior to use. In one embodiment, the catheter is
soaked in a solution including a paraben for a period of time, and
thereby impregnated with the paraben to provide a catheter
featuring resistance to infection. Such soaking solutions
preferably include the paraben at a high concentration. Due to the
solubility limits of parabens in water, high concentrations of
parabens can advantageously be provided by dissolving the paraben
in alcohol or a water/alcohol mixture.
In another form, the present invention provides a kit for locking a
patient's catheter. The kit includes a container having therein a
catheter lock solution comprising citrate and a paraben dispersed
or dissolved therein; and instructions, recorded in a medium, for
infusing the solution into a lumen of an indwelling catheter.
Further objects, features, aspects, forms, advantages and benefits
shall become apparent from the description and drawings contained
herein.
While the actual nature of the invention covered herein can only be
determined with reference to the claims appended hereto, certain
forms and features, which are characteristic of the preferred
embodiments disclosed herein, are described briefly as follows.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a perspective view of one embodiment of a catheter and
syringe for infusing a lock solution into a catheter for use with
the present invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
For the purposes of promoting an understanding of the principles of
the invention, reference will now be made to the embodiments
described herein and specific language will be used to describe the
same. It will nevertheless be understood that no limitation of the
scope of the invention is thereby intended. Any alterations and
further modifications in the described fluids, methods, devices or
kits, and any further applications of the principles of the
invention as described herein, are contemplated as would normally
occur to one skilled in the art to which the invention relates.
In accordance with the invention, a catheter lock solution is used
to provide anticoagulant and antibacterial properties to an
implanted catheter as the lock solution resides in the catheter
between uses. As used herein, the term "lock solution" refers to a
solution that is injected or otherwise infused into a lumen of a
catheter with the intention of allowing at least a portion of a
lock solution to remain in the lumen until it is desired or
required to access that particular lumen again, typically for
additional treatment, i.e., infusion or withdrawal of fluid. It is
desired that at least a portion the lock solution remain in the
lumen for a desired amount of time lasting from about 1 hour to 3
or 4 days or longer. However, frequently the lock solution is
changed on a daily basis during regular care and sterile
maintenance of the indwelling catheter. Use of a lock solution in
accordance with the present invention provides particular
advantages for patients with catheters by inhibiting
catheter-related infections and by preventing catheter
occlusion.
A catheter used in connection with the present invention typically
can either be an acute (temporary) or chronic (long-term) catheter
surgically implanted in an animal. The catheter usually is inserted
into a vein or artery. The catheter is typically used in varying
intervals to administer fluids, nutrients, and medications into the
body. The catheter also can be used to withdraw body fluids, such
as blood for hemodialysis treatment. When not in use, the catheter
remains in its position, commonly an intravascular position, until
a subsequent treatment is performed.
The catheters that may be used in accordance with this invention
include known and commonly used catheters and are readily available
from a variety of commercial sources. The catheters may vary in
configuration and size. One type of catheter commonly used in
accordance with this invention is a tunneled catheter that includes
a cuff for ingrowth of tissue to anchor the catheter. Examples of
catheters that may be used include, but are not restricted to, an
ASH SPLIT CATH and DUOSPLIT by Ash Access Technology, Inc.
(Lafayette, Ind.) and Medcomp (Harleysville, Pa.); Tesio Catheters
by Medcomp; PERM CATH by Quinton Instrument Company (Seattle,
Wash.); and HICKMAN and VAS CATH by Bard, Inc. (Salt Lake City,
Utah). Catheters containing totally subcutaneous ports are also
useful in the present invention; examples include LIFESITE by Vasca
(Topsfield, Me.); and DIALOCK by Biolink, Inc. of (Boston, Mass.).
The catheters are manufactured to function for several months. For
example, TESIO catheters can last for up to four years with proper
intervention. However, in actual practice prior to the present
invention, the catheters have exhibited limited longevity because
of occlusion and/or infection. The catheters frequently must be
removed and/or replaced upon the occurrence of occlusion and/or
infection.
FIG. 1 depicts one example of a catheter 10 for use with this
invention. Catheter 10 is a dual lumen catheter and includes an
outer sheath 12 having a cuff 38 and first and second lumens 14 and
16, respectively. Lumens 14 and 16 extend from distal tip 18
through sheath 12 and exit from sheath 12 at connection 36. Each of
lumens 14 and 16 include releasable clamps 20 and 22, respectively.
Each of lumens 14 and 16 terminate in a threaded end 24 and 26,
which can be threadedly attached to protective end caps 28 and 30,
respectively. Fluids including a lock solution can be infused or
withdrawn from each lumen 14 and 16 by making a Luer connection
between a syringe 34 and the ends 24 and 26 of catheter 10.
Alternatively, fluids can be infused or withdrawn from each lumen
by inserting a needle (not shown) through protective end caps 28
and/or 30 after protective end caps 28 and/or 30 have been
sterilized by cleaning successively, for example with Betadine and
alcohol. As yet another alternative, one or both protective end
caps 28 and 30 can be removed and threaded ends 24 and 26 can be
threadedly attached via a connector (not shown) to lines for
infusion or withdrawal of fluids (not shown). Once a desired
treatment session has been completed, the lumens are typically
flushed with normal saline, after which a lock solution is injected
into each lumen and fresh, sterile protective end caps are placed
on the ends 24 and 26 of the catheter. All procedures are performed
using standard sterile techniques well known to those skilled in
the art. The catheters for use with this invention can be prepared
from a variety of materials, including, for example, silicon,
polyurethane, polyvinyl, silicone, or silastic elastomer.
In one form, the present invention provides a catheter lock
solution including citrate and a paraben dispersed or dissolved
therein. A person of ordinary skill in the art will readily
understand that the term "paraben" is used to refer to an alkyl
ester of p-hydroxybenzoic acid. In one embodiment, the paraben is
selected from methyl paraben, ethyl paraben, propyl paraben, butyl
paraben and a mixture of any two or more of said parabens. In
another embodiment, the paraben is methyl paraben, propyl paraben
or a mixture thereof. The citrate in one preferred embodiment is
provided in the form of a citrate salt such as, for example,
trisodium citrate dihydrate.
In one embodiment, the lock solution comprises citrate and methyl
paraben. The amount of methyl paraben in the solution is limited
only by the solubility limit of the methyl paraben in the aqueous
citrate solution. In an exemplary citrate/methyl paraben catheter
lock solution, the concentration of methyl paraben is from about
0.005 to about 0.5 percent. In another embodiment, the
concentration of methyl paraben is from about 0.01 to about 0.5
percent. As used herein, the term "percent" or the symbol "%" is
intended to refer to a concentration measured in grams per 100
milliliters of final solution.
In an alternative embodiment, the lock solution comprises citrate
and propyl paraben. The amount of propyl paraben in the solution is
limited only by the solubility limit of the propyl paraben in the
aqueous citrate solution. In an exemplary citrate/propyl paraben
catheter lock solution, the concentration of propyl paraben is from
about 0.005 to about 0.5 percent. In another embodiment, the
concentration of propyl paraben is from about 0.01 to about 0.2
percent.
In another preferred embodiment, the lock solution comprises
citrate and a mixture of methyl paraben and propyl paraben. In an
exemplary citrate/methyl paraben/propyl paraben catheter lock
solution, the total concentration of the parabens is from about
0.05 to about 0.6 percent. In another embodiment, the total
concentration of the parabens is from about 0.1 to about 0.3
percent. In yet another embodiment, the concentration of methyl
paraben is from about 0.05 to about 0.5 percent and the
concentration of propyl paraben is from about 0.005 to about 0.5
percent. In still another embodiment, the concentration of methyl
paraben is from about 0.05 to about 0.3 percent and the
concentration of propyl paraben is from about 0.005 to about 0.3
percent. In a particular embodiment that has been found to have
excellent properties, methyl paraben has a concentration of about
0.18 percent and propyl paraben has a concentration of about 0.02
percent in the fluid.
Although it is not intended that the present invention be limited
by any theory whereby it achieves its advantageous results, it is
believed that the citrate prevents coagulation by chelating the
calcium in the adjacent blood. Decreasing the citrate concentration
decreases the effect of calcium to catalyze numerous reactions that
form blood clots. Citrate as an anticoagulant catheter lock is
preferably present at a concentration at least as high as necessary
to significantly decrease the ionized calcium concentration in
blood, even when the lock solution is diluted by blood at the tip
of a catheter. In one preferred embodiment, sodium citrate is
present in a lock solution at a concentration of from about 1.5 to
about 47 percent. In another embodiment, citrate is present at a
concentration of from about 1.5 to about 23 percent. In yet another
embodiment, citrate is present at a concentration of from about 1.5
to about 15 percent. In another embodiment, citrate is present at a
concentration of up to about 20 percent.
The above concentrations are presented as "percent" of mostly
trisodium citrate in water. When various combinations of salts of
citrate are combined, such as trisodium citrate with citric acid,
for example to obtain a certain pH, it is more accurate and helpful
to express the concentration of citrate as a molar concentration,
with a certain percentage of salts being sodium, hydrogen or other
cations. Thus, in one embodiment, citrate is present at a
concentration of at least about 0.004 Molar, more preferably from
about 0.01 to about 1.0 Molar. Another embodiment includes citrate
at a concentration of from about 0.1 to about 0.5 Molar. Yet
another embodiment includes citrate at a concentration of about
0.24 Molar.
At a citrate concentration of 7% by weight, the citrate has a
strong anticoagulant effect in the catheter lock solution. At this
concentration, however, it is believed that citrate alone would not
provide a significant antimicrobial property. The present invention
relates to the discovery, which has been experimentally established
that a mixture of citrate, methyl paraben and propyl paraben has
unexpected and surprisingly effective antibacterial activity when
used as a catheter lock solution in accordance with the present
invention. In a series of tests with multiple microorganism,
solutions including citrate, methyl paraben and propyl paraben
dispersed or dissolved therein effectively killed all species of
bacteria within 1 day (and most within one hour), while a solution
including heparin and a paraben, a solution including saline and a
paraben, a solution including only 7% citrate and a straight saline
solution have little or no effect on the organisms.
Furthermore, the excellent antimicrobial effect exhibited by the
citrate/paraben mixture has surprisingly been found to be
independent of the pH of the solution. In this regard (and as shown
in the Example below), a solution including 7% citrate by weight,
0.18% methyl paraben by weight and 0.02% propyl paraben by weight
was shown to have substantially equal antimicrobial effect on a
wide variety of bacterial species at a pH of about 4.5 and at a pH
of about 6.2. Further information regarding experimental work
involving these solutions is set forth in the Examples below. In a
preferred embodiment of the invention, the pH of the inventive
catheter lock solution is from about 4 to about 8.
In one preferred embodiment, an inventive catheter lock solution
includes citrate (provided, for example, in the form of trisodium
citrate dihydrate) at a concentration of about 7% and a paraben
component having a concentration of about 0.2%. In one preferred
embodiment about 90% of the paraben component is methyl paraben and
about 10% of the paraben component is propyl paraben.
A problem that must be addressed with any catheter lock solution is
that the solutions do not permanently stay within the catheter.
Some of the catheter lock solution exits the end of the catheter
during the infusion (often about 1/3 of the injected volume) when a
volume is injected into the catheter equal to the lumen volume of
the catheter. In addition, the portion remaining in the end of the
catheter is typically washed out slowly by flow of blood through
the side-holes of the catheter (if present). Other lock solution
slowly diffuses from the body of the catheter through the end of
the catheter during the time that lapses between dialysis
treatments.
In the case of concentrated citrate, for example, gravitational
effects also come into play. It is of course understood that the
densities of citrate solutions increase as the concentrations of
citrate therein increase. The relative density of 23% citrate, for
example, is 1.120, which is significantly higher than the relative
density of blood. Thus, when the patient is standing, the segment
of the inner portion of the catheter in the vena cava is vertical.
Gravitational force causes citrate at this concentration to slowly
leave the catheter. In the laboratory, in some types of catheters
positioned vertically (such as the double-D shaped Ash Split Cath
catheters), 23% citrate lock can be shown to slowly exit from the
distal part of the catheter over 3-5 days, into blood or blood
substitute (with the same relative density). In other catheters
(such as cylindrical Tesio catheters) the 23% citrate lock does not
exit over time.
In vitro studies have indicated that the density of a lock solution
is important in determining the length of time that the lock
solution remains in the catheter. The relative density of blood
with hematocrit of 32% is approximately 1.040. If a catheter lock
solution with relative density higher than this is placed into a
catheter positioned vertically, the lock solution will exit from
the catheter at a slow rate. Increasing the viscosity with
polymeric substances such as PEG slows but does not prevent the
egress of the lock solution. Therefore, in certain embodiments of
the invention, the citrate concentration in a lock solution is
selected such that the density of the lock solution is sufficiently
close to the density of the patient's blood that the solution does
not exit the catheter during the lock period to an unacceptable
degree.
It is believed that 7% sodium citrate (0.24 Molar citrate) alone is
the concentration that matches a blood relative density of 1.040.
This concentration of citrate does not have significant
antibacterial effect at neutral or acid pH; however, the
antithrombotic effect of 0.24 Molar citrate will remain very high
even with some diffusion out of the catheter. Not only is the
specific gravity of this solution at or near that of blood, thus
minimizing or eliminating the "running out" of the solution from
the end of a catheter, but is has also been shown to exhibit a
surprisingly high antimicrobial effect when combined with a low
concentration of parabens.
In one aspect of the invention, therefore, a catheter lock solution
comprising citrate and a paraben is provided that has a density of
from about 1.000 to about 1.300 g/ml. In another embodiment, a lock
solution comprising citrate and a paraben has a density of from
about 1.000 to about 1.080 g/ml. In still another embodiment, a
lock solution comprising citrate and a paraben is provided having a
density of from about 1.030 to about 1.050 g/ml. In yet another
embodiment, an inventive lock solution comprising citrate and a
paraben has a density of from about 1.035 to about 1.045 g/ml. It
is understood that the density of a given patient's blood may
differ from the density of the blood of another patient. Thus, the
present invention also contemplates matching the relative density
of a catheter lock solution to within a predetermined tolerance of
the relative density of whole blood of a given patient (such as,
for example, within 0.040 g/ml of the relative density of the
patient's blood). Such density matching is within the purview of a
person of ordinary skill in the art in view of the present
description. Closely matching the densities has the advantageous
effect of aiding in the retention of the catheter lock solution
within the catheter between treatments. When the relative densities
are relatively close, gravitational force does not tend to urge the
catheter lock solution out of the catheter when the patient is
upright. Similarly blood will not enter the catheter when the
catheter is upward directed as in the femoral vein when the patient
is standing (as can happen with a low-density catheter lock such as
heparin).
In another aspect of the invention, the catheter lock solution may
also include an agent to modify viscosity, as described in
International Publication No. WO 00/10385, which is incorporated
herein by reference in its entirety. The presence of a viscosifying
agent is particularly useful, for example, when the relative
density of a given catheter lock solution is not the same as the
density of a patient's blood.
Therefore, in certain preferred embodiments, a lock solution is
provided that comprises citrate, a paraben and one or more agents
to adjust viscosity to help retain the lock within the catheter for
a desired amount of time. It is well known that catheters are
manufactured to have a variety of configurations and lumen
diameters. For example, catheters can include single or double
lumens. The double lumens can be fused adjacent to each other or
they can be concentric. The lumens can have varying cross-sectional
areas and shapes, ranging from substantially circular to
substantially ovoid. As discussed above, a phenomenon common to
most lock solutions is that a portion of the solution at the distal
end of the lumen diffuses into the patient's blood stream and is
replaced in the catheter by blood. The rate of diffusion of a lock
solution from a lumen can be influenced not only by the density of
the lock solution, but also by the cross-sectional shape and area
of the particular lumen(s) and the viscosity of the lock solution.
A lock solution of the present invention is preferably prepared to
have a viscosity and density such that a substantial portion of the
lock solution does not diffuse or flow out of a catheter lumen
under normal circumstances within several days.
Viscosifying agents that can advantageously be selected for use in
accordance with the present invention include those
pharmaceutically acceptable agents known or commonly used in
treatment of animals including humans. Examples include, but are
not limited to, dextran, polyethylene glycol, glycerin, polygeline,
and non-metabolizable sugars such as sorbitol and mannitol and
mixtures of these compounds. Viscosifying agents that increase the
viscosity of a lock solution allow a higher concentration of
citrate to be used without having an unacceptable degree of egress
of the lock solution from the catheter due to high density of the
lock solution.
While it is understood that optimal viscosity and density are
dependent upon the shape and size of a particular lumen, a person
of ordinary skill in the art, in view of the description herein,
can readily determine a desired density and viscosity for a
particular catheter without undue experimentation. It is of course
understood that the need for viscosifying agents is reduced or
eliminated in a lock solution having a relatively lower
concentration of citrate and a density closely matched to that of
blood. The antiseptic effect of the citrate, which is reduced by
the reduction in the citrate concentration, is achieved by the
inclusion of a paraben or a mixture of parabens in an amount
whereby the citrate and paraben together exhibit an antiseptic
effect.
An inventive lock solution can be prepared to include a variety of
other pharmaceutically acceptable agents. For example, the lock
solution can include salts, such as, for example, sodium chloride
or other sodium salts. The lock solution can also include a variety
of other antibacterial, antimicrobial and anticoagulant agents.
Such antibacterial and antimicrobial agents are well known to those
skilled in the art and can include, without limitation, gentamicin,
vancomycin, and mixtures of these agents. Additional anticoagulant
agents that can be included in an inventive catheter lock solution
include, for example, heparin, urokinase, tissue plasminogen
activation (tPA) and mixtures of these agents. When the
anticoagulant includes heparin, the heparin is preferably present
at a concentration of from about 100 units/ml to about 10,000
units/ml.
By "pharmaceutically acceptable", it is meant that the lock
solution and the included salts and other additives which are,
within the scope of sound medical judgment, suitable for use in
contact with tissues of humans and lower animals without undue
toxicity, irritation, allergic response, and the like, and are
commensurate with the reasonable benefit/risk ratio. It is also
typically necessary that a composition be sterilized to reduce the
risk of infection. For example, pharmaceutically acceptable salts
are well-known in the art, and examples can be found in S. M. Berge
et al. described in detail in J. Pharmaceutical Science, 66:1-19,
1977.
Another example of a pharmaceutically acceptable agent that can be
included in a lock solution made or selected in accordance with the
invention is a photo-oxidant, such as, for example, methylene blue.
As used herein, the term "photo-oxidant" is defined to mean a
photo-oxidant that has antimicrobial properties when present at a
suitable concentration in an inventive solution. The use of
methylene blue and other photo-oxidants in a catheter lock solution
is discussed in U.S. Patent Application Publication No. US
2004/0092890, which is hereby incorporated herein by reference in
its entirety. The present inventors have discovered that the
inclusion of a photo-oxidant in a catheter lock solution along with
citrate and a paraben results in enhanced antimicrobial properties.
As such, in another excellent aspect of the present invention,
there are provided catheter lock solutions that include citrate, a
paraben and a photo-oxidant dissolved in the solution. In one
preferred embodiment, the photo-oxidant is methylene blue.
Alternative photo-oxidants that can be selected for use in
accordance with the invention include, without limitation, Rose
Bengal, hypericin, methylene violet, proflavine, riboflavin,
rivanol, acriflavine, toluide blue, trypan blue, neutral red and
mixtures thereof.
In one embodiment of the invention, the concentration of the
photo-oxidant in the solution is up to about 1500 mg/100 ml. In
another embodiment, the concentration of the photo-oxidant in the
fluid is from about 1 to about 1500 mg/100 ml. In still another
embodiment, the concentration of the photo-oxidant in the fluid is
from about 1 to about 1000 mg/100 ml. In yet another embodiment,
the concentration of the photo-oxidant in the fluid is from about 1
to about 100 mg/100 ml. In a further embodiment, the concentration
of the photo-oxidant in the fluid is from about 1 to about 50
mg/100 ml. In another embodiment, the concentration of the
photo-oxidant in the fluid is about 10 mg/100 ml.
In addition to enhancement of the antimicrobial properties of a
catheter lock solution, a photo-oxidant is advantageous in that it
imparts a color to the solution. The present application also
contemplates the use of other coloring agents in catheter lock
solutions made or used in accordance with the invention. Coloring
agents can be used, for example, to provide a safety function,
indicating to observers that the catheter contains a catheter lock
solution. For example, methylene blue at a concentration of 10
mg/100 ml has a dark blue color in a syringe, and a noticeably blue
color within the clear external segments of the catheter. Over
time, the methylene blue solution lightly stains the inside of
catheters made of polyurethane or silicone, but the injected lock
solution still makes the segments noticeably darker in color.
Therefore the presence of the lock solution is recognizable. In
addition, it is possible to use a system of color coordination in
which different coloring agents are used to identify, for example,
different citrate concentrations, different paraben concentrations
or mixtures, or perhaps lock solutions that include other
additives, such as, for example, anticoagulants or antibiotics.
In addition to inventive catheter lock solutions, as described
above, the present invention also provides methods of inhibiting
infections in an animal having an indwelling intravascular
catheter. In one aspect, therefore, the invention provides a method
that includes selecting a patient having an indwelling catheter
defining a lumen therethrough, and infusing an aqueous catheter
lock solution into the lumen, the solution comprising citrate and a
paraben dispersed or dissolved therein. In a preferred manner of
practicing the invention, the method comprises infusing an amount
of the lock solution that is from about 80% to about 120% of the
internal volume of the catheter being locked.
Once a lock solution is infused into the lumen of a catheter in
accordance with the invention, it is preferably allowed to remain
until it is time to access that particular catheter or lumen again.
It is desirable to remove the catheter lock before starting the
dialysis procedure or using the catheter for fluid infusion,
especially if the catheter lock solution includes heparin.
In other aspects of the invention, the catheter lock solution
containing citrate and a paraben may be injected into catheters
used for access to other body spaces besides veins or arteries. For
example, catheters used in peritoneal dialysis access the
peritoneum (the space defined by the peritoneal membrane and
exterior to the organs in the abdomen). These catheters also have a
risk of bacterial and fungal contamination. After draining and
infusing peritoneal dialysate solutions, a lock solution including
citrate and a paraben is infused into the catheter. Other catheters
with risk of infection include catheters in the urinary bladder,
the cerebral spinal fluid (around the central nervous system) and
the subcutaneous space (under the skin).
The present invention also contemplates the pretreatment of a
catheter to provide an infection-resistant catheter. In an
advantageous aspect of the invention, therefore, a catheter
selected for implantation into a patient, such as, for example,
into a vascular site of a patient, can be pretreated with a
solution including a paraben to coat and impregnate the catheter
surfaces with the paraben, thereby providing an infection-resistant
catheter. Generally, it is sufficient to soak the catheter in an
excess volume of an aqueous paraben solution, followed by washing
in water or in a solution mimicking physiological conditions of use
to remove non-absorbed material. In a preferred embodiment,
however, it is desirable to soak the catheter in a high
concentration of paraben that exceeds the solubility limits of the
paraben in water. In one preferred embodiment, the paraben is
dissolved in alcohol or a water/alcohol mixture, and the catheter
is soaked therein. The catheter, pretreated in this manner, has an
increased resistance to infection when it is placed into position,
particularly when a solution comprising citrate or a solution
comprising citrate and a paraben is placed therein.
It is also contemplated that a wide variety of other polymeric
medical devices can be treated as described above. For example,
medical devices that are amenable to coating and impregnation by a
paraben solution include non-metallic materials such as
thermoplastic or polymeric materials. Examples of such materials
are rubber, plastic, polyethylene, polyurethane, silicone, Gortex
(polytetrafluoroethylene), Dacron (polyethylene tetraphthalate),
Teflon (polytetrafluoroethylene), latex, elastomers and Dacron
sealed with gelatin, collagen or albumin. Devices especially suited
for application of the antimicrobial combinations of this invention
include, for example, peripherally insertable central venous
catheters, dialysis catheters, long term tunneled central venous
catheters, peripheral venous catheters, short-term central venous
catheters, arterial catheters, pulmonary artery Swan-Ganz
catheters, urinary catheters, long term urinary devices, tissue
bonding urinary devices, vascular grafts, vascular catheter ports,
wound drain tubes, hydrocephalus shunts, peritoneal catheters,
pacemaker capsules, small or temporary joint replacements, urinary
dilators, heart valves and the like.
One embodiment of the present invention, therefore, is a method for
impregnating a non-metallic medical implant with a paraben
comprising the steps of forming an aqueous solution of an effective
concentration of a paraben to inhibit the growth of bacterial and
fungal organisms; and applying the solution to at least a portion
of a medical implant under conditions where the paraben permeate
the material of the medical implant. The paraben solution can have
a wide variety of concentrations, depending upon the amount of
paraben one desires to become impregnated in the catheter or other
device. In addition, the amount of time that the catheter or other
device is soaked in the solution can be varied to vary the degree
of impregnation. Typically it will be desired to soak the catheter
for at least about an hour, and often significantly longer.
After the impregnated implant is removed from the solution, and
optionally allowed to dry, the implant is preferably rinsed with a
liquid to remove excess paraben from the surface thereof. It is of
course understood that the invention can be used in certain
embodiments to pre-treat a portion of a catheter or other device.
In the case of an intravascular catheter, for example, it may be
desirable to pre-treat only the lumen of the catheter. This can be
done by simply placing a pretreatment solution into the lumen of
the catheter rather than soaking the entire catheter.
Alternatively, it is possible to pre-treat only a portion of a
catheter that will reside within a patient's artery or vein, or to
pre-treat only the portion that lies transcutaneously.
In another aspect, the invention involves an infusion device for
infusing a lock solution into a lumen of a catheter. The infusion
device includes a syringe and a pharmaceutically acceptable lock
solution contained within the syringe, the lock solution including
citrate and a paraben dispersed or dissolved therein. In a
preferred embodiment, the syringe containing the lock solution is
sterilized. The syringe can be advantageously used to infuse a
catheter lock solution into a catheter that has an injection port
affixed thereto by attaching a needle to the syringe and injecting
the needle into the port. Alternatively the syringe can be used by
uncapping a catheter and attaching the syringe directly to the
catheter.
In another aspect of the invention, there is provided a catheter
lock kit. In one preferred embodiment, a kit includes a container
having therein a catheter lock solution, the catheter lock solution
comprising citrate and a paraben dispersed or dissolved therein;
and instructions, recorded in a medium, for infusing the solution
into a lumen of an indwelling catheter.
As will be appreciated by those of ordinary skill in the art, in
one form of the invention there has been described an aqueous
catheter lock solution comprising citrate and a paraben dispersed
or dissolved therein. The citrate and the paraben preferably have
concentrations effective to eliminate infection and to reduce the
likelihood of subsequent infections. The solution can include, for
example and without limitation, a member selected from the group
consisting of methyl paraben, ethyl paraben, propyl paraben, butyl
paraben and mixtures of any two or more of these.
In one embodiment of the invention, the solution comprises methyl
paraben. In a preferred embodiment described herein, the
concentration of methyl paraben in the solution is from about 0.005
to about 0.5 percent. In another embodiment, the solution comprises
propyl paraben. In a preferred embodiment, the concentration of
propyl paraben in the solution is from about 0.005 to about 0.5
percent. In yet another embodiment, the solution comprises a
mixture of methyl paraben and propyl paraben. In a preferred
embodiment, the concentration of methyl paraben in the solution is
from about 0.05 to about 0.5 percent and the concentration of
propyl paraben in the solution is from about 0.005 to about 0.5
percent. In another preferred embodiment described herein, the
concentration of methyl paraben in the solution is about 0.18% by
weight and the concentration of propyl paraben in the solution is
about 0.02% by weight.
The concentration of citrate in the solution is preferably at least
as high as the calcium concentration in a patient's blood. In one
preferred embodiment, the concentration of citrate in the solution
is from about 1.5 to about 47% by weight. In another preferred
embodiment, the concentration of citrate in the solution is from
about 1.5 to about 23% by weight. In still another preferred
embodiment, the concentration of citrate in the solution is from
about 1.5 to about 15% by weight. In yet another preferred
embodiment, the concentration of citrate in the solution is about
7% by weight.
In one catheter lock solution described herein, the citrate has a
concentration of from about 1.5 to about 15 percent and the paraben
has a concentration of from about 0.005 to about 0.6 percent. In
another catheter lock solution, the concentration of citrate in the
solution is from about 1.5 to about 15% by weight and the paraben
concentration in the solution is from about 0.05 to about 0.3
percent. In yet another catheter lock solution, the concentration
of citrate in the solution is about 7% by weight and the
concentration of paraben in the solution is about 0.2% by
weight.
In certain preferred embodiments, the citrate is provided in the
solution in the form of a citrate salt. In one preferred
embodiment, the citrate is provided in the solution in the form of
trisodium citrate dihydrate.
In certain preferred embodiments described herein, a catheter lock
solution is provided in which the pH of the solution is from about
4 to about 8. In other preferred embodiments, the relative density
of the solution is from about 1.000 to about 1.300 g/ml. In another
embodiment, the relative density of the solution is from about
1.000 to about 1.080 g/ml.
In other preferred embodiments, catheter lock solutions are
described that further include a viscosifying agent. The
viscosifying agent can be, for example, a member selected from the
group consisting of dextran, polyethylene glycol, glycerin,
polygeline, non-metabolizable sugars such as sorbitol and mannitol,
and mixtures of these compounds.
In yet another form of the invention, there is described a catheter
lock solution that includes citrate and a paraben dispersed or
dissolved therein, and also includes a photo-oxidant dissolved in
the solution. The photo-oxidant can be, for example and without
limitation, a member selected from the group consisting of
methylene blue, Rose Bengal, hypericin, methylene violet,
proflavine, riboflavin, rivanol, acriflavine, toluide blue, trypan
blue, neutral red and mixtures thereof. In a preferred embodiment
of the invention, the photo-oxidant comprises methylene blue.
In one embodiment described herein, the concentration of methylene
blue or other photo-oxidant in the solution is up to about 1500
mg/100 ml. In another embodiment, the concentration of the
methylene blue or other photo-oxidant in the fluid is from about 1
to about 1500 mg/100 ml. In still another embodiment, the
concentration of the methylene blue or other photo-oxidant in the
fluid is from about 1 to about 1000 mg/100 ml. In yet another
embodiment, the concentration of the methylene blue or other
photo-oxidant in the fluid is from about 1 to about 100 mg/100 ml.
In a further embodiment, the concentration of the methylene blue or
other photo-oxidant in the fluid is from about 1 to about 50 mg/100
ml. In another embodiment, the concentration of the methylene blue
or other photo-oxidant in the fluid is about 10 mg/100 ml.
In another aspect of the invention, there is described a method for
treating a patient that includes: (1) selecting a patient having an
indwelling catheter defining a lumen therethrough; and (2) infusing
into the lumen an aqueous catheter lock solution made or selected
in accordance with the present invention. In one manner of
practicing this inventive method, the catheter is selected from the
group consisting of an intravascular catheter and a body cavity
catheter. In a preferred embodiment, the lumen of the catheter has
an internal volume and said infusing includes infusing an amount of
the lock solution that is from about 80% to about 120% of the
internal volume.
In yet another aspect, the invention provides an infusion device
for infusing a lock solution into a lumen of a catheter. The device
includes a syringe; and a pharmaceutically acceptable lock solution
contained within the syringe. The lock solution can be any one of a
wide variety of lock solutions provided in accordance with the
present invention, in all of its various aspects and embodiments
described herein. In one preferred embodiment, the syringe
containing the lock solution is sterilized.
In still another aspect of the invention, there is described a kit
for locking a patient's catheter. The kit includes (1) a container
having therein a catheter lock solution; and (2) instructions,
recorded in a medium, for infusing the solution into a lumen of an
indwelling catheter. The lock solution is one of a wide variety of
lock solutions provided in accordance with the present invention,
in all of its various aspects and embodiments described herein. In
one preferred embodiment, the catheter is selected from the group
consisting of an intravascular catheter and a body cavity catheter.
In another preferred embodiment, the lumen of the catheter has an
internal volume and instructions include instructions to infuse an
amount of the lock solution of from about 80% to about 120% of the
internal volume.
In a further aspect, the invention provides a method of treating
animals having a surgically implanted catheter. The method includes
infusing into said catheter a pharmaceutically acceptable lock
solution comprising a bactericidal component, wherein the
bactericidal component consists essentially of citrate and a
paraben. In one embodiment, the bactericidal component consists
essentially of citrate, a paraben and a photo-oxidant. In another
embodiment, the bactericidal component does not include an
antibiotic.
The invention will be further described with reference to the
following specific Examples. It will be understood that these
Examples are intended to be illustrative and not restrictive in
nature.
EXAMPLE 1
A catheter lock solution was prepared in accordance with the
invention to include citrate at a concentration of 7%, by weight
(provided as trisodium citrate), methyl paraben at a concentration
of 0.18%, by weight and propyl paraben at a concentration of 0.02%
by weight. The target pH of the catheter lock solution was 4.5, and
the actual pH of the solution during the test was measured at 4.58.
This solution was put into contact with colonies of multiple
species of bacteria by injection of bacteria spores into the
prepared solution, and the bacteria was scored periodically (at 60
minutes, 24 hours, 48 hours and 72 hours) to determine the number
of colony forming units (CFU) per milliliter. The data is set forth
below in Table I:
TABLE-US-00001 TABLE I Test Recovery Level (CFU/ml) Microorganism 0
Time 60 min. 24 hours 48 hours 72 hours S. aureus 500,000 <100
<100 <100 <100 ATCC 33591 E. coli 650,000 <100 <100
<100 <100 ATCC 35218 E. coli 460,000 <100 <100 <100
<100 ATCC 25922 P. aeruginosa 290,000 <100 <100 <100
<100 ATCC 27853 C. alibicans 560,000 290,000 <100 <100
<100 ATCC 10231 E. faecalis 610,000 <100 <100 <100
<100 ATCC 376 S. epidermidis 440,000 <100 <100 <100
<100 ATCC 12228
EXAMPLE 2
A catheter lock solution was prepared in accordance with the
invention to include citrate at a concentration of 7%, by weight
(provided as trisodium citrate), methyl paraben at a concentration
of 0.18%, by weight and propyl paraben at a concentration of 0.02%
by weight. The target pH of the catheter lock solution was 6.2, and
the actual pH of the solution during the test was measured at 6.26.
This solution was put into contact with colonies of multiple
species of bacteria by injection of bacteria spores into the
prepared solution, and the bacteria was scored periodically (at 60
minutes, 24 hours, 48 hours and 72 hours) to determine the number
of colony forming units (CFU) per milliliter. The data is set forth
below in Table II:
TABLE-US-00002 TABLE II Test Recovery Level (CFU/ml) Microorganism
0 Time 60 min. 24 hours 48 hours 72 hours S. aureus 500,000 5,900
<100 <100 <100 ATCC 33591 E. coli 650,000 <100 <100
<100 <100 ATCC 35218 E. coli 460,000 <100 <100 <100
<100 ATCC 25922 P. aeruginosa 290,000 <100 <100 <100
<100 ATCC 27853 C. alibicans 560,000 300,000 <100 <100
<100 ATCC 10231 E. faecalis 610,000 100 <100 <100 <100
ATCC 376 S. epidermidis 440,000 100 <100 <100 <100 ATCC
12228
EXAMPLE 3
Comparative Example
A catheter lock solution was prepared to include heparin with
preservatives at a concentration of 2,500 units/ml. This lock
solution was prepared by combining 1 ml of 5,000 unit/ml heparin,
1.5 mg/ml methyl paraben and 0.15 mg/ml propyl paraben with 1 ml
0.9% sterile saline. This solution was put into contact with
colonies of multiple species of bacteria by injection of bacteria
spores into the prepared solution, and the bacteria was scored
periodically (at 60 minutes, 24 hours, 48 hours and 72 hours) to
determine the number of colony forming units (CFU) per milliliter.
The data is set forth below in Table III:
TABLE-US-00003 TABLE III Test Recovery Level (CFU/ml) Microorganism
0 Time 60 min. 24 hours 48 hours 72 hours S. aureus 500,000 550,000
530,000 >3,000,000 >3,000,000 ATCC 33591 E. coli 650,000
610,000 450,000 196,000 106,000 ATCC 35218 E. coli 460,000 420,000
130,000 166,000 116,000 ATCC 25922 P. aeruginosa 290,000 310,000
14,800 700 200 ATCC 27853 C. alibicans 560,000 380,000 550,000
270,000 360,000 ATCC 10231 E. faecalis 610,000 640,000 60,000
1,370,000 1,710,000 ATCC 376 S. epidermidis 440,000 390,000 113,000
44,000 9,500 ATCC 12228
EXAMPLE 4
Comparative Example
A saline-only (0.85%) catheter lock solution was prepared. The
saline solution was put into contact with colonies of multiple
species of bacteria by injection of bacteria spores into the
prepared solution, and the bacteria was scored periodically (at 60
minutes, 24 hours, 48 hours and 72 hours) to determine the number
of colony forming units (CFU) per milliliter. The data is set forth
below in Table IV:
TABLE-US-00004 TABLE IV Test Recovery Level (CFU/ml) Microorganism
0 Time 60 min. 24 hours 48 hours 72 hours S. aureus 500,000 820,000
>3,000,000 >3,000,000 >3,000,000 ATCC 33591 E. coli
650,000 620,000 >3,000,000 >3,000,000 >3,000,000 ATCC
35218 E. coli 460,000 780,000 >3,000,000 >3,000,000
>3,000,000 ATCC 25922 P. aeruginosa 290,000 189,000
>3,000,000 >3,000,000 >3,000,000 ATCC 27853 C. alibicans
560,000 550,000 234,000 340,000 430,000 ATCC 10231 E. faecalis
610,000 700,000 >3,000,000 >3,000,000 >3,000,000 ATCC 376
S. epidermidis 440,000 570,000 80,000 7,800 5,900 ATCC 12228
EXAMPLE 5
Comparative Example
A catheter lock solution was prepared to include methyl paraben at
a concentration of 0.09%, by weight and propyl paraben at a
concentration of 0.01% by weight (in saline, without citrate). This
solution was put into contact with colonies of multiple species of
bacteria by injection of bacteria spores into the prepared
solution, and the bacteria was scored periodically (at 60 minutes,
24 hours, 48 hours and 72 hours) to determine the number of colony
forming units (CFU) per milliliter. Based upon periodic visual
inspections of the samples over a period of 72 hours, the
paraben-only catheter lock solution was observed to have no
significant antibacterial effect on the growth of colonies of S.
aureus (ATCC 33591); E. coli (ATCC 35218); E. coli (ATCC 25922); P.
aeruginosa (ATCC 27853); C. alibicans (ATCC 10231); and E. faecalis
(ATCC 376). The paraben-only solution did have an antibacterial
effect upon S. epidermidis (ATCC 12228), upon which the solution
had a significant antibacterial effect within the first 24-hour
period.
EXAMPLE 6
Two catheter lock solutions were prepared in accordance with the
invention. The first included citrate at a concentration of 7%, by
weight (provided as trisodium citrate), methyl paraben at a
concentration of 0.18%, by weight, propyl paraben at a
concentration of 0.02% by weight. The second included the same
citrate at a concentration of 7%, by weight (provided as trisodium
citrate), methyl paraben at a concentration of 0.18%, by weight,
propyl paraben at a concentration of 0.02% by weight, plus
methylene blue at a concentration of 0.01% by weight. The target pH
of both catheter lock solutions was 6.2, and the actual pH of the
solutions during the test was measured at 6.2. These solutions were
put into contact with colonies of E. faecalis bacteria by injection
of bacteria spores into the prepared solution, and the bacteria was
scored periodically (at 0 minutes, 10 minutes, 20 minutes, 40
minutes and 60 minutes) to determine the number of colony forming
units (CFU) per milliliter. The data is set forth below in Table
V:
TABLE-US-00005 TABLE V Microorganism/ Recovery Level (CFU/ml) Lock
Solution 0 Time 10 min. 20 min. 40 min. 60 min. E. faecalis
13,130,000 4,500,000 16,700,000 6,350,000 235,000 Parabens only E.
faecalis 1,300,000 64,000 <100 <100 <100 Parabens plus
methylene blue
EXAMPLE 7
Two catheter lock solutions were prepared in accordance with the
invention. The first included citrate at a concentration of 7%, by
weight (provided as trisodium citrate), methyl paraben at a
concentration of 0.045%, by weight, propyl paraben at a
concentration of 0.005% by weight. The second included the same
citrate at a concentration of 7%, by weight (provided as trisodium
citrate), methyl paraben at a concentration of 0.045%, by weight,
propyl paraben at a concentration of 0.005% by weight, plus
methylene blue at a concentration of 0.015% by weight. The target
pH of both catheter lock solutions was 6.2, and the actual pH of
the solutions during the test was measured at 6.2. These solutions
were put into contact with colonies of E. faecalis bacteria by
injection of bacteria spores into the prepared solution, and the
bacteria was scored periodically (at 0 minutes, 1 hour, 24 hours,
48 hours and 72 hours) to determine the number of colony forming
units (CFU) per milliliter.
The data is set forth below in Table V:
TABLE-US-00006 TABLE VI Microorganism/ Recovery Level (CFU/ml) Lock
Solution 0 Time 1 hr. 24 hr. 48 hr. 72 hr. E. faecalis 26,180,000
2,845,000 2,800 213 <100 Parabens only E. faecalis 12,100,000
332 <100 <100 <100 Parabens plus methylene blue
EXAMPLE 8
Manufacturing of a Representative Catheter Lock Solution
Method
A catheter lock solution is formulated as a sterile mixture of USP
grade chemicals in the following concentrations: 7% citrate
solution by weight, 0.18% methyl paraben by weight and 0.02% propyl
paraben. The solution is designed to have a relative density of
1.035 to 1.045, and pH of about 6.2. The citrate solution is
prepared at the desired pH (6.2) by mixing 428 ml of 0.24 M
trisodium citrate dihydrate solution (70.58 g/L) and 72 ml of 0.24
M anhydrous citric acid solution (46.10 g/L). The final solution is
obtained by adding 0.18 g of methyl paraben and 0.02 g of propyl
paraben per 100 ml of citrate solution in the actual batch size.
The solution is stored at room temperature.
The bulk solution is then pumped into an aseptic filling area,
passing through a secondary and then primary 0.2 micron sterilizing
filter before flowing into a sterilized surge type or pressure type
vessel. The sterilized solution in the sterile vessel flows to the
filler where light resistant, type 1 glass vials (5 mL, Kimble,
type 1 Borosilicate Glass Amber Vial, 13-mm Finish, Untreated) are
conveyed and filled with the predetermined fill volume. The filled
vials are then conveyed to the stoppering location where stoppers
(West, 13 mm, 4432/50 Rubber Stopper) are placed in the vials. The
vials are then conveyed to a capping machine which applies aluminum
crimp seals with flip off caps to each vial (West, 13 mm Aluminum
Seal, Flip-off Button). Overseals (crimped caps) are applied in a
capping area outside of the aseptic processing area.
The filled, stoppered and capped vials are then inspected for
visible particulate matter and other defects.
The starting materials for making the solution of this embodiment
are readily available commercially.
EXAMPLE 9
Using an Inventive Catheter Lock Solution
At the end of a patient's hemodialysis treatment each lumen of the
catheter is filled with the lock solution in an amount equal to the
fill volume of the catheter lumen. Each lumen is filled to the tip
using a quick bolus technique for the first 2/3 of the injected
volume, and slow infusion (over 10 seconds) for the last 1/3 of the
injected volume.
The catheter lock solution is removed before each dialysis
procedure, by attaching a syringe to each catheter lumen and
removing 1 mL more than the catheter lumen volume (about 3 mL
total), discarding the syringe, then flushing the catheter with 5
mL of sterile normal saline.
While the invention has been illustrated and described in detail in
the drawings and foregoing description, the same is to be
considered as illustrative and not restrictive in character, it
being understood that only the preferred embodiments have been
shown and described and that all changes and modifications that
come within the spirit of the invention are desired to be
protected.
* * * * *
References